Phase 3 Study of Efficacy and Safety of the XaraColl® Bupivacaine Implant After Hernioplasty: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 3 Study of Efficacy and Safety of the XaraColl® Bupivacaine Implant After Hernioplasty (NCT02525133), a randomized phase 3 study. The primary outcome is SPI24.

2. Clinical Question

3. Trial Design

This was a Phase 3, randomized, parallel-group, placebo-controlled study of postoperative pain in adults scheduled for unilateral inguinal hernioplasty through an open, tension-free technique. The registry describes the study as multicenter and double-blind in the official title, and records quadruple masking. The study was completed.

The registry records enrollment of 319. The primary outcome results are reported for the modified intent-to-treat population, which required randomization, receipt of any dose of study intervention, and at least one pain-intensity score before hospital discharge, as needed to calculate the endpoint. The arm counts for the primary outcome are 207 for XaraColl and 105 for placebo. The registry record does not report why these outcome counts differ from the enrollment figure.

Participants assessed pain intensity from 0 through 72 hours after surgery using the 11-point numerical rating scale. The primary endpoint covered 0 to 24 hours. Five secondary outcomes are listed: TOpA24, TOpA48, TOpA72, SPI48, and SPI72. Results for those secondary outcomes are not reported in the registry record.

The registry gives a study start date of 2015-09-05 and a primary completion date of 2016-04-22. It describes an expected maximum study duration for each participant of up to 60 days, including screening, surgery and implantation, treatment, and follow-up. The registry record does not report further detail about site locations, the randomization procedure, or the conduct of masking.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: modified intent-to-treat - The mITT population consisted of randomized subjects who received any dose of INL-001 or placebo and who had at least 1 NRS PI score prior to hospital discharge, as needed, to compute SPI.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: The modified intent-to-treat (mITT) population consisted of all randomized subjects who received any dose of INL-001 or placebo and who had at least 1 NRS PI score prior to hospital discharge

6. Primary Endpoint

The registry lists the primary outcome as SPI24, measured over 0 to 24 hours.

The primary endpoint, SPI24, is the time-weighted sum of pain-intensity scores from Time 0 through 24 hours. Participants rated pain on an 11-point numerical rating scale, where 0 indicated “no pain” and 10 indicated “worst pain possible.” The endpoint is expressed in units on a scale, with a stated minimum of 0 and maximum of 240.

SPI24 incorporates both the recorded pain-intensity values and the time between assessments. As described in the registry, the score is calculated by summing pain intensity multiplied by the interval between successive time points. The record characterizes this as the area under the curve of pain intensity calculated with the trapezoidal rule. In practical terms, the score represents accumulated pain intensity over the specified period rather than a single rating at one moment.

A time-weighted measure is used to retain information about how pain ratings vary across the assessment period and when those ratings occur. A lower SPI24 mean corresponds to a lower accumulated score on this measure; it does not, by itself, describe any individual participant’s experience. The primary endpoint was compared once at a two-sided significance level of 0.05, so the registry states that no multiplicity adjustment was necessary for that primary efficacy analysis.

7. Results Posted in the Registry

• XaraColl: mean 88.30 versus 116.20 on control; difference -27.90 (95% CI -38.48 to -17.32), standardized effect d = -0.61; z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: SPI24 is a numerical score that summarizes pain intensity over time. The registry reports the mean and standard deviation in each arm and a mean difference comparing XaraColl with placebo. A mean difference expresses the distance between the two arm averages in the endpoint’s own units. Its sign depends on the order of the comparison: the reported value of -27.9 is for XaraColl versus placebo, so it represents a lower posted mean in the XaraColl arm.

What does the endpoint calculation represent?

General statistical explanation: a time-weighted sum uses measurements and the intervals between them, rather than treating every rating as if it occurred at the same time or reducing the series to one isolated rating. The registry describes SPI24 as the sum of pain intensity multiplied by the time between successive assessments and as the area under the pain-intensity curve using the trapezoidal rule. That construction gives a summary of the measured pain-intensity trajectory during the endpoint window. It remains a summary: it does not preserve every feature of each participant’s sequence of ratings.

What do the mean and standard deviation describe?

The mean is the average endpoint value within an arm. The standard deviation describes how spread out values are around that arm’s mean. The posted means are 88.3 for XaraColl and 116.2 for placebo; the corresponding standard deviations are 47.01 and 44.04. General statistical explanation: greater spread means individual scores vary more around the group average. Standard deviation is not the same as the uncertainty in the estimated mean, and it is not a confidence interval for an individual score.

How should the mean difference and p-value be read?

The mean difference is -27.9, and its reported 95% confidence interval extends from -38.48 to -17.32. The interval gives a range of values compatible with the comparison under the statistical procedure and its assumptions. The p-value, reported as p < 0.001, describes how incompatible the observed result is with the equal-mean null hypothesis under the analysis assumptions. It is not the probability that the null hypothesis is true, nor does it measure the probability that the result will repeat. Statistical significance does not by itself establish clinical importance.

The registry says the primary efficacy variable was compared once at a two-sided 0.05 level, and therefore no multiplicity adjustment was necessary for that primary analysis. A two-sided comparison allows for a difference in either direction rather than specifying only one direction. The registry record does not report more detail about the statistical test or model used to obtain the comparison and interval.

What is the analysis population?

The primary analysis used the modified intent-to-treat population. It included randomized participants who received any dose of INL-001 or placebo and had at least one pain-intensity score before hospital discharge, as needed to compute SPI. This definition is narrower than simply identifying everyone enrolled or randomized: it requires intervention receipt and an available rating relevant to the endpoint. The registry record does not report the detailed disposition of participants or reasons that a primary score might not have been available.

General statistical explanation: analysis-population definitions matter because they specify which participants contribute to the estimate. A modified intent-to-treat definition can preserve some features of randomized-group comparison while excluding participants who do not meet the stated post-randomization requirements. The record’s definition should therefore be kept in view when interpreting the posted estimate; it should not be silently treated as an analysis of every enrolled participant.

What cannot be assessed from the recorded methods?

The registry record does not report details of the statistical model, missing-data procedures, sensitivity analyses, or a fuller analysis plan. It lists five secondary outcomes, but results for those outcomes are not reported in the registry record. The record also does not report a rationale for the planned enrollment or the trial’s original sample-size assumptions. Those omissions prevent an assessment of how alternative analysis choices might affect the primary estimate or how the planned enrollment was determined. General statistical explanation: transparent methods help readers understand the assumptions behind an estimate, assess its robustness, and distinguish prespecified analyses from later exploratory work. The posted summary statistics support interpretation of the reported comparison, but cannot replace details that are not reported.

10. Confidence Intervals and Precision

The reported mean difference for XaraColl versus placebo is -27.9, with a 95% confidence interval from -38.48 to -17.32. This interval describes uncertainty around the estimated difference, rather than the range of individual participant scores. Its endpoints are both below zero, matching the direction of the posted mean difference: the estimated average SPI24 is lower in the XaraColl arm.

General statistical explanation: a confidence interval is produced by a method that, over repeated use under its assumptions, would capture the target parameter at the stated rate. It is not a probability statement that the particular fixed parameter has a 95% chance of lying inside this already-calculated interval. The interval’s width reflects precision: a narrower interval indicates a more precise estimate than a wider interval, all else equal. Precision is distinct from clinical importance.

The arm standard deviations, 47.01 for XaraColl and 44.04 for placebo, describe variability in observed scores, not the uncertainty interval for the mean difference. The interval for the comparison is the relevant reported measure of precision for that contrast. The registry record does not provide additional confidence intervals for the separate arm means or results for the listed secondary outcomes.

The interval’s placement below zero supports a direction for the posted statistical comparison, but it does not determine whether the difference is meaningful to participants. The registry record does not report a threshold for clinical importance on the SPI24 scale. Nor does the interval alone resolve questions about missing observations, the model used, or whether results would be similar under other analysis choices; those details are not reported in the registry record.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are illustrations based on the observed mean difference, not the original enrollment plan. Each figure is the number of participants per arm for 80% power or the number of participants per arm for 90% power, under the stated planning assumptions. They are not total event counts: the record’s planning note distinguishes participant counts per arm for non-time-to-event outcomes from total event counts for time-to-event outcomes, and SPI24 is a continuous outcome.

The assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set as a stated fraction of the observed effect. Planning for 100% of the observed effect gives 43 participants per arm for 80% power and 58 participants per arm for 90% power. Planning for 75% of the observed effect gives 76 participants per arm for 80% power and 102 participants per arm for 90% power. Planning for 50% of the observed effect gives 171 participants per arm for 80% power and 229 participants per arm for 90% power.

In plain terms, the 80% column gives the planned number per arm under these assumptions for an 80% chance of detecting the specified effect using the stated statistical test framework; the 90% column gives the corresponding planning number for a higher target chance. Smaller effects require more participants per arm under these assumptions, as reflected by the increasing figures as the target fraction decreases. These are not observed power calculations; they are planning illustrations using the observed effect, and the trial’s own original design assumptions are not reported in the registry record.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -27.900; pooled standard deviation σ = 46.035.
2. n = 2 × (1.96 + 0.842)² × 46.035² / -27.900² = 42.7, rounded up to 43 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -27.9                      # observed difference in means
sigma <- 46.0349764292186                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2525133)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 43 (80% power), 58 (90% power)
 75% of observed effect: n per arm = 76 (80% power), 102 (90% power)
 50% of observed effect: n per arm = 171 (80% power), 229 (90% power)
power.t.test: 43.7 
Simulated power at n = 43 per arm: 0.794 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry states that SPI24 was compared once at a two-sided significance level of 0.05. On that basis, it says no multiplicity adjustment was necessary for the primary efficacy analysis. This statement is specifically about the primary comparison; it should not be extended to unreported analyses.

Five secondary outcomes are listed: TOpA24, TOpA48, TOpA72, SPI48, and SPI72. Their analysis results are not reported in the registry record. The record therefore does not establish whether those outcomes were tested, how any multiple comparisons were handled, or how their results relate to the primary comparison. The number of outcome measures recorded is 6, and no analyses are posted for the secondary outcomes.

The primary analysis population is described as modified intent-to-treat. It included randomized participants who received any dose of INL-001 or placebo and had at least one pain-intensity score prior to hospital discharge, as needed to compute SPI. The endpoint counts are 207 for XaraColl and 105 for placebo. The registry record does not report a fuller participant flow, reasons for missing or unavailable ratings, or the handling of any missing values in the primary endpoint.

General statistical explanation: missing-data methods matter because an endpoint may be unavailable for some randomized participants, and the assumptions used to handle that absence can affect an estimate. Without information about missingness and the analysis procedure, readers cannot determine whether the reported comparison is robust to different plausible assumptions. The registry record also does not report sensitivity analyses, a detailed statistical plan, or whether any interim analyses were conducted. Those matters should be treated as unreported rather than inferred from the posted primary result.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: acute myocardial infarction (0.9%), abdominal pain (0.9%), groin pain (0.9%), atrial fibrillation (0.5%), appendicitis (0.5%).

The registry reports serious adverse-event figures for the safety groups: 3 in the XaraColl group, with 208 at risk, and 3 in the placebo group, with 107 at risk. The record also reports deaths of 0 in the XaraColl group and 1 in the placebo group. These are descriptive registry counts. No risk comparison or causal interpretation is implied by reporting them.

The registry lists serious adverse-event terms with percentages: Acute myocardial infarction, 0.9%; Abdominal pain, 0.9%; Groin pain, 0.9%; Atrial fibrillation, 0.5%; and Appendicitis, 0.5%. The record does not specify in these listed terms whether the percentages are arm-specific or give further detail about how the terms were counted. They should not be assigned to one arm without that information.

Other adverse events are also recorded, with 118 in the XaraColl group and 76 in the placebo group. These figures are distinct from the serious adverse-event counts. The registry record does not report definitions, event-level detail, severity breakdowns, or a fuller account of follow-up for these safety figures. Counts alone do not establish whether an event was caused by an intervention, and they do not provide a complete assessment of safety.

15. What the Result Does, and Does Not, Mean

The primary result is a comparison of mean SPI24, the time-weighted sum of pain-intensity ratings from 0 to 24 hours, in the modified intent-to-treat population. The posted mean was 88.3 for XaraColl and 116.2 for placebo. The reported mean difference was -27.9, with a 95% confidence interval from -38.48 to -17.32 and p < 0.001. These figures describe a lower average accumulated pain-intensity score in the XaraColl arm for this endpoint and analysis.

The result does not mean that every participant in one arm had a lower score than every participant in the other arm. The standard deviations, 47.01 and 44.04, show variation within both arms. A group average and its confidence interval do not describe each person’s outcome, and the endpoint summarizes assessments over a defined period rather than capturing every aspect of postoperative experience.

The registry’s statistical evidence does not by itself establish clinical importance. The record does not report a threshold for a meaningful SPI24 difference, nor does it provide results for the five listed secondary outcomes. The primary result also cannot be extended automatically to other procedures, populations, treatment periods, or pain measures. The registry’s population definition, outcome window, and comparator are part of what the estimate means.

The result is not a treatment recommendation. A p-value is not a measure of the probability that the intervention is effective, and a confidence interval is not a prediction interval for individual responses. The safety figures are descriptive, and the registry record does not provide sufficient detail to infer causation from the listed events. The appropriate interpretation is limited to the posted comparison and the information recorded about its analysis.

16. Why This Trial Matters Statistically

This trial illustrates how a clinical endpoint can be a constructed summary rather than a single observed rating. SPI24 combines pain-intensity ratings with the time between successive assessments. That approach makes the endpoint sensitive to both rating values and their timing, so understanding the measure’s definition is essential when interpreting an arm difference.

The result also shows why a mean difference should be read alongside its confidence interval and the variability in each arm. The reported difference is -27.9, and its 95% confidence interval runs from -38.48 to -17.32. The standard deviations of 47.01 and 44.04 describe variation in the observed endpoint values. Together, these statistics communicate direction, scale, uncertainty, and spread; a p-value alone would not convey all of those features.

Another statistical issue is the distinction between enrollment and the analysis population. The study enrollment is recorded as 319, while the primary outcome counts are 207 for XaraColl and 105 for placebo. The defined modified intent-to-treat population requires intervention receipt and at least one relevant pain-intensity score. Since participant disposition and missing-data handling are not reported in the registry record, interpreting the estimand requires attention to that population definition.

Finally, the registry identifies a single primary comparison and states that no multiplicity adjustment was necessary for it, while five secondary outcomes are listed without posted results. This illustrates the importance of separating the primary finding from outcomes whose results and multiplicity handling are not reported. Statistical interpretation depends not only on the numerical estimate, but also on the endpoint, population, comparison, and level of analysis detail available.

17. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary comparison is reported for a modified intent-to-treat population rather than all enrolled participants. The registry defines that population by randomization, receipt of any dose, and availability of at least one pain-intensity rating before hospital discharge as needed to compute SPI. It does not report a detailed participant flow or explain the difference between enrollment of 319 and the primary outcome counts of 207 for XaraColl and 105 for placebo. Reasons for absent or unusable ratings are not reported in the registry record.

The registry record does not report the detailed statistical model, missing-data procedure, sensitivity analyses, or a full analysis plan. It also does not report the trial’s original sample-size assumptions or rationale for enrollment. The posted planning illustrations based on the observed effect are not a substitute for those original design details.

SPI24 is a time-weighted summary over 0 to 24 hours. Although assessments were described through 72 hours, results for the five listed secondary outcomes are not reported in the registry record. The primary result therefore does not describe later outcome periods in the posted results. The registry also does not report a threshold for clinical importance on this scale, limiting interpretation of the magnitude beyond its statistical units.

The safety information is limited to recorded counts, at-risk counts, deaths, and selected serious-event terms with percentages. Definitions, detailed event-level information, and further attribution details are not reported in the registry record. These constraints do not negate the reported statistics, but they limit broader conclusions from them.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Phase 3 Study of Efficacy and Safety of the XaraColl® Bupivacaine Implant After Hernioplasty — NCT02525133.
• Registry record last updated 2021-01-08; status last verified 2021-01.
• Results first posted 2021-01-08.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

21. Record Summary

The record describes a completed Phase 3, randomized, parallel-group, placebo-controlled study of XaraColl after open unilateral inguinal hernioplasty. The study is listed as multicenter and quadruple-masked, while the official title describes it as double-blind. Enrollment was 319. The study start date was 2015-09-05, and the primary completion date was 2016-04-22. The sponsor was Innocoll.

The primary endpoint was mean SPI24, a time-weighted pain-intensity score from 0 to 24 hours. The reported means were 88.3 for XaraColl and 116.2 for placebo; the mean difference was -27.9, with a 95% confidence interval from -38.48 to -17.32 and p < 0.001. Five secondary outcomes are listed, but their results are not reported in the registry record. The posted safety information includes serious adverse-event counts and deaths, with further analysis details not reported.